Classical cannabinoids such as the marijuana derived cannabinoid Δ9-tetrahydrocannabinol, (Δ9-THC) produce their pharmacological effects through interaction with specific cannabinoid receptors in the body. So far, two canabinoid receptors have been characterized: CB1, a central receptor found in the mammalian brain and peripheral tissues and CB2, a peripheral receptor found only in the peripheral tissues. Compounds that are agonists or antagonists for one or both of these receptors have been shown to provide a variety of pharmacological effects. See, for example, Pertwee, R. G., Pharmacology of cannabinoid CB1 and CB2 receptors, Pharmacol. Ther., (1997) 74:129-180 and Di Marzo, V., Melck, D., Bisogno, T., DePetrocellis, L., Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action, Trends Neurosci. (1998) 21:521-528.
In addition to acting at the cannabinoid receptors, cannabinoids such as Δ9-THC also affect cellular membranes, thereby producing undesirable side effects such as drowsiness, impairment of monoamine oxidase function and impairment of non-receptor mediated brain function. The additive and psychotropic properties of some cannabinoids also limit their therapeutic value.
Arachidonylethanolamide (anandamide) is an endogenous lipid that binds to and activates the CB1 cannabinoid receptor with approximately equal affinity to that of Δ9-THC.
Anandamide also exhibits biochemical and pharmacological properties similar to that of Δ9-THC, albeit with a longer onset time and shorter duration of action. The exact physiological role of anandamide, a cannabinoid agonist, is still not clearly understood. It is known that an enzyme called “anandamide amidase” hydrolyzes anandamide. It is presumed that the magnitude of action and relatively short duration of action of anandamide is due to a rapid inactivation process consisting of carrier-mediated transport into cells followed by intra-cellular hydrolysis by anandamide amidase.
Presently known anandamide analogues show susceptibility towards enzymatic hydrolysis and/or have low receptor affinity. There is considerable interest in developing analogs of anandamide possessing high CB1 receptor affinity and/or metabolic stability. Such analogs may offer a rational therapeutic approach to a variety of disease states in which elevation of anandamide analog levels may bring about a more favorable response with fewer side effects and greater metabolic stability than direct activation of CB1 receptors by anandamide.